DPP-4 Inhibitors Have Different Effects on Endothelial Low-Grade Inflammation and on the M1-M2 Macrophage Polarization Under Hyperglycemic Conditions.

PURPOSE

We explored the anti-inflammatory role of the DPP-4 inhibitor teneligliptin, using sitagliptin as comparator, in different in vitro models of low-grade inflammation (LGI), evaluating the hyperglycemia-induced endothelial inflammation, the macrophage polarization, and the endothelium-macrophage interaction.

METHODS

The effects of DPP-4 and its inhibitors on macrophage polarization were evaluated in THP-1 cells by measuring mRNA expression of M1-M2 markers. HUVEC cells were used to analyze the effects of DPP-4 inhibitors on endothelial inflammation under normal and high glucose conditions. To evaluate the link between eNO and M1-M2 polarization, HUVECs were transfected with eNOS siRNA and co-cultured with THP-1 cells. The effects of DPP-4 inhibitors on macrophage polarization and eNO content were evaluated in a co-culture model of differentiated THP-1 cells + HUVECs under normal glucose (NG), high glucose (HG) and high metabolic memory (HM) conditions.

RESULTS

DPP-4 regulated M1/M2 macrophage polarization. Teneligliptin reduced M1 and enhanced M2 macrophage phenotype under DPP-4 stimulation, and attenuated hyperglycemia-induced endothelial inflammation. In THP-1 cells co-cultured with eNOS depleted HUVECs, M1 markers were enhanced, while M2 reduced, indicating an important role of eNO in polarization to M2 phenotype. In the co-culture model with HUVECs exposed to HG and HM, teneligliptin reduced M1 and enhanced M2 population, by increasing eNO levels. The anti-inflammatory effects of sitagliptin were not observed in these LGI models.

CONCLUSION

Teneligliptin, but not sitagliptin, has anti-inflammatory effects in the various LGI models, by promoting a switch from M1 toward M2 phenotype and by decreasing hyperglycaemia-induced endothelial inflammation, suggesting that effects for LGI are different among DPP-4 inhibitors.